麻豆传媒

Cannabidiol (Epidiolex) may alter blood levels of several commonly used antiepileptic drugs in adults and children, according to an open-label study published in

Cannabidiol showed interactions with topiramate (Topamax), rufinamide (Banzel), and clobazam (Onfi) in adult and pediatric patients, reported Tyler Gaston, MD, of the University of Alabama at Birmingham, and colleagues. Serum levels of zonisamide (Zonegran) and eslicarbazepine (Aptiom) also increased in adults with increasing cannabidiol doses.

In addition, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were significantly higher in participants who took valproate (Depakote) with the cannabis derivative.

"A perception exists that since cannabidiol is plant-based, it is natural and safe, and while this may be mostly true, our study shows that cannabidiol, just like other antiepileptic drugs, has interactions with other seizure drugs that patients and providers need to be aware of," Gaston said in a statement.

The interaction between cannabidiol and clobazam already had been established, she noted, but there was little published data showing how cannabidiol might alter other seizure medications in humans.

In an ongoing, open-label study, the researchers looked at 81 patients -- 39 adults and 42 children -- with treatment-resistant epilepsy. They defined "treatment-resistant" as failing to respond to a total of four or more antiepileptic drugs at adequate dose, including at least one trial of two concomitant treatments. Patients who had a history of substance abuse or addiction, had used medical marijuana or a cannabidiol-based product in the past 30 days, or had AST or ALT elevation ≥ 5 times the upper limit of normal, could not participate.

The average age of patients in the adult group was 29; in the pediatric group, it was 10. Both groups used an average of 3 anti-epileptic drugs at enrollment. Among the 81 patients, 30 used lamotrigine (Lamictal), 27 used clobazam, 25 used clonazepam (Klonopin), 22 used valproate, 20 used topiramate, 20 used levetiracetam (Keppra), and 20 used lacosamide (Vimpat). A total of 19 antiepileptic drugs were evaluated over the course of 1 year.

All patients received Epidiolex at doses starting at 5 mg/kg/day, split between the morning and evening. Patients were instructed to take cannabidiol at the same time as their other antiepileptic drugs.

Researchers obtained baseline drug levels, then evaluated participants every 2 weeks during active titration of the cannabidiol dose, with less frequent appointments when doses were not adjusted. At each follow-up clinic visit, doses could be titrated in 5 mg/kg/day increments to a maximum of 50 mg/kg/day, with adjustments based on patients' responses to treatment and tolerability. If patients had worsening seizures or side effects, their doses could decreased by phone, but increases were made only in person.

In both adult and pediatric patients, investigators found significant increases in serum levels of topiramate, rufinamide, and N-desmethylclobazam (a clobazam metabolite) as cannabidiol doses increased (all P<0.01). They also saw significant increases in serum zonisamide (P=0.02) and eslicarbazepine (P=0.04) in adult patients only. No pediatric patients in the study took eslicarbazepine.

With the exception of clobazam and N-desmethylclobazam, all mean level changes were within accepted therapeutic ranges, the researchers noted.

A total of 6 of 12 adults and 8 of 15 children who took clobazam complained of sedation at least once during the study, which led to clobazam doses being decreased, but not discontinued.

In a subanalysis of liver function tests, AST and ALT levels were significantly higher in adult and pediatric participants taking valproate with cannabidiol (P<0.01). When the combination was discontinued, AST/ALT levels normalized quickly.

The researchers saw no significant interactions with other antiepileptic drugs. Of particular interest, they noted, was the lack of interaction between cannabidiol and clonazepam, despite the fact that clobazam and clonazepam metabolize through similar pathways.

"This important study shows that cannabidiol, which is emerging as a promising antiepileptic medicine in humans, can have clinically significant drug interactions," Orrin Devinsky, MD, of NYU Langone Medical Center, who was not involved in the study, told 麻豆传媒.

"The major findings are supported by prior observations -- that cannabidiol raises levels of the clobazam n-desmethyl metabolite and can increase ALT and AST, especially in patients taking concomitant valproate," Devinsky said. "The other findings should be considered preliminary and await verification."

Limitations of the study included its small sample size of patients taking individual antiepileptic drugs, which the researchers partly offset by the large number of observations of each patient over the course of a year. The naturalistic design of the study also created a significant amount of noise in the data that the researchers could not account for in their analysis.

The investigation is part of an ongoing, open-label, expanded access program in the state of Alabama to study cannabidiol as therapy for epilepsies that are difficult to control, including Dravet and Lennox-Gastaut syndromes.

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